Over the past decade, the use of MRI to study multiple sclerosis (MS) has lead to substantial advances in understanding the disease process. Disease activity as detected by new lesions on T2-weighted images or contrast enhancing lesions on T1-weighted images have established that the level of activity seen on MRI is considerably greater than that seen clinically. Further, MRI has become an important and powerful tool for the assessment of the effect of new experimental therapies in MS. Recent work continues to focus on defining the natural history of the disease using MRI and in examining the effect of experimental treatments on disease activity as measured by MRI. Specifically, recent studies have focused on the following questions;1. What is the natural history of new lesions in MS identified by contrast enhancement and other MRI measures? Components of this uestion include a comparison of disease activity using contrast enhancement, lesion load n T2-weighted images and advanced imaging techniques including agnetization transfer imaging and proton spectroscopy.2. What is the level of disease activity seen in patients who are early in the relapsing remitting course of the disease? 3. Interferon beta 1b is approved for the treatment of MS and has been shown to produce over the short term a reduction in disease activity as measured by MRI. Does the treatment effect persist and what, if any, effect does the development of neutralizing antibodies have on the efficacy of the treatment?4. What effect do treatments that are chosen to target various aspects of the MS lesion have on disease activity and which MRI measures are best for studying treatments that target the various stages of the lesion? Serial studies of patients with early, relapsing-remitting MS using contrast enhanced MRI have shown that nearly two thirds of the patients have evidence of active new lesion formation. Recent studies in the NIB have examined the evolution of the MS lesion using imaging techniques that measure tissue destruction such as lesion load on T2-weighted images or T1 hypointensities, alterations in magnetization transfer ratios and alterations seen using proton spectroscopy. Findings have demonstrated that progression of disease as measured by overall burden of disease increases during the early phase of the disease. However, only a modest correlation can be found between the frequency of acute enhancing lesions and the level of accumulated disease burden suggesting that distinct mechanisms may contribute to lesion progression. In addition, some patients showing a marked reduction in new disease activity as measured by contrast enhancing lesions continue to have progression of disease as measured by T2 lesion load or T1 hypointensities. Studies of the effect of experimental treatments on various stages of the MS lesion can provide valuable information at several levels. In addition to providing evidence that a treatment may be effective in the disease, changes in the evolution of the MS lesion on MRI during the use of an experimental treatment can help establish the mechanism involved in the pathogenesis of the lesion. Consequently, recent studies in the NIB have focused on treatments that are thought to modify different aspects of lesion development. Particular focus has been placed on the ability of an altered peptide, modeled on the sequence of an immunodominant epitope of myelin basic protein to modify disease. Preliminary results have shown that dministration of the altered peptide can produce an increase in T cells eactive with MBP and that his increase is associated with increased disease activity on MRI. This observation provides very important support for the role of MBP or other myelin specific T cells in the pathogenesis of MS. Future studies will focus on the ability to modify this therapy in a manner that will result in down regulation of potentially pathogenic T cells. - Multiple sclerosis, MRI, Therapy, Trial design - Human Subjects